Reversal of thymic stromal lymphopoietin-induced airway inflammation through inhibition of Th2 responses.
Lung-specific thymic stromal lymphopoietin (TSLP) expression is sufficient for the development of an asthma-like chronic airway inflammatory disease. However, the nature of the downstream pathways that regulate disease development are not known. In this study, we used IL-4- and Stat6-deficient mice to establish the role of Th2-type responses downstream of TSLP. IL-4 deficiency greatly reduced, but did not eliminate, TSLP-induced airway hyperresponsiveness, airway inflammation, eosinophilia, and goblet cell metaplasia, while Stat6 deficiency eliminated these asthma-like symptoms. We further demonstrate, using the chronic model of TSLP-mediated airway inflammation, that blockade of both IL-4 and IL-13 responses, through administration of an anti-IL-4R alpha mAb, reversed asthma-like symptoms, when given to mice with established disease. Collectively these data provide insight into the pathways engaged in TSLP-driven airway inflammation and demonstrate that simultaneous blockade of IL-4 and IL-13 can reverse established airway disease, suggesting that this may be an effective approach for the therapy of Th2-mediated inflammatory respiratory disease.
Zhou
Baohua
B
Immunology Program, Benaroya Research Institute, Seattle, WA 98101, USA. zhoub@iupui.edu
Headley
Mark B
MB
Aye
Theingi
T
Tocker
Joel
J
Comeau
Michael R
MR
Ziegler
Steven F
SF
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002908:Chronic Disease; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology / Q000633:toxicity*; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; C508598:IL4 protein, human; C508600:IL6 protein, human; D018793:Interleukin-13; D015850:Interleukin-6; D015847:Interleukin-4; D000094632:Thymic Stromal Lymphopoietin